Chronic stress is involved in the development of several different diseases in the nervous, endocrine and immune systems. Stressors of various types, e.g. psychological, physical and biological, abound. Sustained stress related to work appears to be an increasingly important factor for the development of both physical and mental illness (see Tennant, Journal of Psychosomatic Research, 2001, 51(5), 697-704; and Vahtera, Lancet, 1997, 350 (9085), 1124-1128).
In Sweden alone, public expenditure for sick-leave has more than doubled over a few years, and, in 2003, the number of persons on long-term sick leave (i.e. more than 30 days) had increased to an all-time high. Much of this dramatic increase appears to be due to stress-related affective illness. The question remains whether mild or moderate stress-induced depression should be seen as a purely psychological disorder, or whether the characteristic syndrome of fatigue, tension and dysphoria has physical connotations.
The physiological pathways that lead from prolonged stress to exhaustion and depression are likely to involve both the hypothalamus-pituitary-adrenal axis and other endocrine systems, as well as the immune system (see Folkow et al, Acta Physiologica Scandinavica, 1997, 161). The exact sequence of events in the brain-endocrine-immune, systems under chronic stress is not well known in humans, but recent progress in immunology has lead to increasing focus on the links between cytokines and depressive illnesses.
Cytokines are low molecular weight proteins or glycoproteins that were initially characterised as communication molecules of the immune system. They can be secreted by a number of different cell types and play a key role in the regulation of the immune system and the co-ordination of the host response to injury and infection. Cytokines produce their actions by binding to specific high-affinity cell surface receptors. The range of actions displayed by individual cytokines can be broad and diverse and is dependent on the receptor. Receptors can be soluble and can bind to the cytokine, in turn inhibiting the binding of the cytokine to the cell surface receptor, blocking its biological. Cytokines operate within a complex network and may act synergistically or antagonistically. They can influence the production of other cytokines from other cell types. Initially, it was thought that the cytokines were restricted to the immune system but it has since been demonstrated that they are also involved in signalling in the central nervous and endocrine systems.
In 1991, Smith formulated the macrophage theory of depression. This hypothesis proposed that excessive secretion of macrophage cytokines such as IL-1, TNFa and IFNg, were a cause of some cases of major depression. Both before and after the proposal of this theory, others have reported that when previously psychiatrically healthy individuals have been treated with exogenous cytokines they develop depressive-like symptoms. This has also been observed in patients being treated with cytokines such as IFNg, where 80% of patients reported fatigue from moderate to severe intensity. The same has been found with administration of certain cytokines to experimental animals. Many studies have measured the circulating levels of cytokines in relation to one or more specific stressors, but these studies have revealed conflicting results due to sample sizes being small and the use of different assays making results difficult to interpret. In vitro cytokine secretion by stimulation of the peripheral blood lymphocytes has also been studied in relation to stress and depression. These studies have almost exclusively focused on IL-6, IL-1, TNFa and IFNg. Again, the results have varied and no definite pattern has emerged.
Cytokines can be measured by either immunoassay or bioassay. Bioassays measure the functional activity of cytokines and require that some measure of biological activity be recorded. Bioassays can lack specificity as other cytokines present in the sample can give the same response in the assay or because the sample may contain inhibitors which block them. Also, if the cytokines have been proteolytically degraded they will not retain biological activity. Immunoassays are based on an antibody that recognises a small portion of the cytokine and therefore most are very specific for the cytokine being measured. It is possible for biologically inactive cytokines and proteolytically degraded cytokines to be measured. Until very recently most of the cytokine immunoassay measurements have been performed using individual ELISAs.
At present, no reliable markers of chronic stress and related disorders (e.g. stress-related depression) have been identified.